Whole blood collected from a donor is used for transfusion, as is, only in rare cases, but is commonly separated into components, such as an erythrocyte preparation, thrombocyte preparation, blood plasma preparation, and the like to be stored for transfusion. Since micro aggregate and leukocytes included in these blood preparations cause various side effects during blood transfusion, there have been increasing occasions wherein these undesirable components are removed before blood transfusion. The need for leukocyte removal has widely been recognized particularly in recent years. Removal of leukocytes from all kinds of blood preparations for blood transfusion before using for transfusion has been legislated in some European countries.
The most common method of removing leukocytes from blood preparations is by processing blood preparations using a leukocyte removing filter. Conventionally, blood preparations have been processed using a leukocyte removing filter in many cases at the bedside when blood transfusion is performed. In recent years, however, to improve quality control of leukocyte-free preparations and efficiency of leukocyte removal operations, it is more common to process the blood preparations in blood centers before storing the blood preparations.
A blood collection-separation set, typically consisting of two to four flexible bags, a tube connecting these bags, an anticoagulant, an erythrocyte preservation solution, a blood-collecting needle, and the like has been used for collecting blood from a donor, separating the blood into several blood components, and storing the blood components. A system in which a leukocyte removing filter is incorporated into such a blood collection-separation set has been widely used as an optimum system for the above-mentioned pre-storage leukocyte removal. Such a system is called a closed system or an integrated system and the like. Such a system is disclosed in JPA 1-320064, WO 92/20428, and the like.
Conventionally, a filter made from nonwoven fabric or porous filter elements packed in a hard container of polycarbonate or the like has been widely used as a leukocyte removing filter. However, because the container used in such a filter d, International Publication Number W098/51799oes not have gas permeability, it has been difficult to use a vapor sterilization method, which is a widely accepted sterilization method in blood collection-separation sets. In a closed system, leukocytes are first removed from the whole blood preparation after collecting the blood. Then, after the leukocyte removing filter is separated, the leukocyte-free blood is centrifuged for separation into various components. In another type of closed system, the whole blood is first centrifuged to be divided into various components, and then the leukocytes are removed. In the latter system, the leukocyte removing filter is also centrifuged together with the blood collection-separation set. In this instance, a hard container may damage bags and tubes, or the container itself may not withstand the stress and may collapse during centrifugation.
To solve this problem, flexible leukocyte removing filters, in which the container is made of the same or a similar material having superior flexibility and high vapor permeability as used for the bags of the blood collection-separation set, have been developed.
These filters are broadly classified into the type in which the filter elements are welded to a sheet-like flexible frame, which is then welded to a housing material (EP 0 526 678, JPA11-216179) and the type in which the flexible container is directly welded to the filter elements (JPA 7-267871, WO 95/17236).
The former type may be hereinafter called the frame welding type and the latter may be called the container welding type.
When processing blood in these types of leukocyte removing filters, the bag containing a blood preparation to be processed, connected to the blood inlet port of the filter via a tube, is placed at a height 20-100 cm higher than the filter to allow the blood preparation to pass through the filter by action of gravity. After filtration, the blood preparation is stored in a collection bag connected to the blood outlet port of the filter via a tube. During filtration, a pressure loss is caused due to the resistance of the filter element, whereby the pressure in the space on the inlet side of the filter is maintained positive. In the case of the filter attached to a flexible container, the flexibility of the container itself makes the container swell like a balloon due to the positive pressure, thereby pressing the filter element against the outlet port side container. Specifically, a force acting to separate the filter element from the container or the sheet-like frame is always applied to the joining sections of these parts.
In the case of centrifuging the leukocyte removing filter together with the blood collection-separation set, a force acting to separate the filter element from the sheet-like frame or the flexible container may also be applied to the joining sections of these parts. As an example, the centrifuge operation using a one-liter-cylindrical centrifuge cup, which is typically employed in the United States and other countries, will be described. A hypothetical system consisting of a blood bag made of soft polyvinyl chloride containing 570 ml of a whole blood preparation treated for anti-coagulation, a blood processing filter, a bag made of soft polyvinyl chloride containing about 100 ml of an erythrocyte preservation solution, an empty bag for transferring platelet-rich plasma after centrifugation, and an empty bag to store the blood after processing with the blood processing filter arranged in this centrifuge cup in that order to be centrifuged will be discussed. Tubes made of soft polyvinyl chloride to connect the bags to the filter are appropriately arranged between the bags and the filter. The bags and the filter are pressed to the bottom of the centrifuge cup due to the centrifugal force. The bag containing the whole blood preparation and the bag containing an erythrocyte preservation solution are deformed causing them to swell due to the centrifugal force. As a result, the flexible blood processing filter placed between the two blood bags may be crushed by the blood bags or may be deformed into a configuration conforming to the blood bags. Although the mechanism differs from the above case in which the container swells like a balloon, as a result, the same force acting to separate the filter element from the sheet-like frame or the flexible container is applied.
The soft polyvinyl chloride and polyolefin, widely used as materials for containers or frames, exhibit only slight adhesion to the materials popularly used for filter elements such as polyester fibers and polyurethane porous materials. For these reasons, the joining parts have a problem of being easily separated by a comparatively small force. However, the above-mentioned prior art documents, including EP 0 526 678, Japanese Patent Application Laid-open Publication No.11-216179, Japanese Patent Application Laid-open Publication No. 7-267871, and WO 95/17236, or the like, disclosing flexible filters have neither realized this problem nor described the methods of overcoming the problem.
As a matter of fact, commercially available frame attachment type filters do not necessarily have sufficient resistance to the force acting to separate the joining parts of the filter element and the frame. These filters have a risk of invalidating filtration due to detachment of the filter element from the frame during use.
Although there are few commercially available container welding type filters, such filters also have a risk of container breakage or leaking due to the same reasons of separating the filter element from the container during use.
Beside the usual filter operation utilizing gravity, the filter may be compulsory primed with blood by pressing or squeezing the bag containing the blood preparation to be filtered by hand (hereinafter may be called “squeezing”) or may be operated at a high speed by applying a high pressure using a pump. For these reasons, a filter with superior resistance to pressure and separation has been desired.
Furthermore, during the common filter operation utilizing gravity, a flexible container swells like a balloon due to the positive pressure applied to the blood inlet side of the filter as mentioned above. In this instance, the internal filter element bends by being pressed toward the outlet port side container. On the other hand, the space between the outlet port side container and the filter element tends to move toward the bag for storing the processed blood, which is located 50-100 cm lower than the filter by being caused to descend due to the weight of blood in the tube connected to the outlet port. A negative pressure is created by this action, whereby the outlet port side flexible container tends to be caused to adhere to the filter element. Specifically, the filter element is known to closely adhere to the outlet port side container by the double forces, whereby blood flow is obstructed.
As a means for solving this problem, a method of inserting a soft polyvinyl chloride tube called as “a connecting rod” between the filter element and outlet port side container to prevent adherence (EP 0526 678), a method of inserting a screen made of nit fiber (WO 95/17236), a method of preventing adhesion by providing irregularities with a depth of 0.2-2 mm on the internal surface of the soft container (Japanese Patent Application Laid-open Publication No. 11-216179), and other methods have been proposed. However, as described in Japanese Patent Application Laid-open Publication No. 11-216179, the method of inserting a connecting rod or a screen has been considered to have a risk of inducing defective welding of the container if the other materials are inserted. Although the method disclosed in Japanese Patent Application Laid-open Publication No. 11-216179 has been proposed as a measure for solving the problem in the method of inserting a connecting rod or a screen, the solution of the problem was limited to the case in which a soft container is welded with a flexible sheet-like filter. Specifically, although irregularities on the internal surface of the container do not cause a problem for welding the container material with the sheet frame material, the irregularities on the internal surface of the container may cause defective welding when the container material is directly welded with the filter element. Thus, the method was not necessarily satisfactory.